We propose to define the expression and function of the adenosine receptors (ARs) in the sino-atrial node (SAN) pacemaker complex in order to elucidate the role of adenosine signaling in heart rate regulation in failing and non-failing human hearts. The overall objective of the study is to understand the role of adenosine and ARs in SAN dysfunction and arrhythmias during heart failure (HF). Our central hypothesis is that SAN dysfunction in HF results from adenosine-dependent remodeling and signaling. We will use an integrated approach to study normal physiologic and HF-induced remodeling processes in canine and human hearts to delineate the role of adenosine in the normal and pathologic function of the SAN. The complementary canine studies are designed to provide a framework for the targeted, efficient study of the human SAN. We have the expertise, experimental model, and human tissue access to evaluate our hypothesis that AR signaling is critical for both normal SAN function, as well as HF-induced SAN arrhythmias. Preliminary studies support the aims, feasibility of the experimental approaches, and the validity of the canine model as a surrogate for human SAN - now directly demonstrated by new pilot studies. We are well prepared to undertake this project because the Dr. Fedorov (P.I.) has unique optical mapping expertise to evaluate human SAN structure and function; this, combined with the expertise of Dr. Carnes (Co-P.I.) with a clinically relevant model of heart failure isolated myocyte physiology (ion currents) will permit an integrated approach to this problem. Identifying the spatial, structural and signaling elements contributing to abnormal SAN function will delineate the susceptible components causing potentially lethal arrhythmias. This will permit development of a novel 'blueprint' for SAN function and dysfunction, providing a foundation for the development of highly targeted and effective treatments for human arrhythmias originating in the SAN pacemaker complex.